Prostaglandin E2 is a mediator of the inflammatory process but little is known of the endogenous factors that tend to limit the inflammatory process. We have demonstrated that an inhibitor(s) of prostaglandin synthesis is released in psoriatic plaques during therapy with coal tar and ultraviolet light, and in cutaneous lesions characterized histologically by epidermal disruption. This was the first time that natural inhibitors were reported as occurring in inflamed tissues. We postulate that these substances diffuse downwards to limit the inflammatory process in the dermis. Our proposal is directed at characterizing endogenous inhibitors of prostaglandin synthesis, studying their relationship to inflammatory dermatologic disease, elucidating biochemical pathways involved in their synthesis and developing new anti-inflammatory agents based on knowledge acquired through the study of these inhibitory substances. A human model has been devised to study the time course of elaboration of the inhibitor(s) and a guinea pig model has been developed for large scale purification and characterization of the factor(s). From preliminary in vitro data, we propose that prostaglandin F2 alpha is one of the endogenous factors released during epidermal damage and that it inhibits the inflammatory process. Support for this hypothesis will be obtained by direct measurement of prostaglandin F2 alpha and of prostaglandin E2 9-ketoreductase activity, the enzyme that converts prostaglandin E2 into prostaglandin F2 alpha, in tissues characterized by the presence of inhibitor(s) of prostaglandin synthesis.